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?2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis.

ABSTRACT: Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify ?2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.

SUBMITTER: Smith LK

PROVIDER: S-EPMC4529371 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis.

Smith Lucas K LK He Yingbo Y Park Jeong-Soo JS Bieri Gregor G Snethlage Cedric E CE Lin Karin K Gontier Geraldine G Wabl Rafael R Plambeck Kristopher E KE Udeochu Joe J Wheatley Elizabeth G EG Bouchard Jill J Eggel Alexander A Narasimha Ramya R Grant Jacqueline L JL Luo Jian J Wyss-Coray Tony T Villeda Saul A SA

Nature medicine 20150706 8

Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor ...[more]

PMID: 26147761

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Project description:As the population ages, an increasing number of people suffer from age-related cognitive impairment. However, the mechanisms underlying this process remain unclear. Here, we found that S-nitrosoglutathione reductase (GSNOR), the key enzyme that metabolizes intracellular nitric oxide (NO) and regulates S-nitrosation, was significantly increased in the hippocampus of both aging humans and mice. Transgenic mice overexpressing GSNOR exclusively in neurons showed cognitive impairment in behavioral tests, including the Morris water maze, fear conditioning, and the Y-maze test. We also found that GSNOR transgenic mice have LTP defects and lower dendrite spine density, whereas GSNOR knock-out mice rescued the age-related cognitive impairment. Analysis of S-nitrosation showed significantly decreased hippocampal CaMKII? S-nitrosation in naturally aged mice and GSNOR transgenic mice. Consistent with the change in CaMKII? S-nitrosation, the accumulation of CaMKII? in the hippocampal synaptosomal fraction, as well as its downstream signaling targets p(S831)-GLUR1, was also significantly decreased. All these effects could be rescued in the GSNOR knock-out mice. We further verified that the S-nitrosation of CaMKII? was responsible for the CaMKII? synaptosomal accumulation by mutating CaMKII? S-nitrosated sites (C280/C289). Upregulation of the NO signaling pathway rescued the cognitive impairment in GSNOR transgenic mice. In summary, our research demonstrates that GSNOR impairs cognitive function in aging and it could serve as a new potential target for the treatment of age-related cognitive impairment. In contrast to the free radical theory of aging, NO signaling deficiency may be the main mediator of age-related cognitive impairment.SIGNIFICANCE STATEMENT This study indicated that S-nitrosoglutathione reductase (GSNOR), a key protein S-nitrosation metabolic enzyme, is a new potential target in age-related cognitive impairment; and in contrast to the free radical theory of aging, NO signaling deficiency may be the main cause of this process. In addition, increased GSNOR expression during aging decreases S-nitrosation of CaMKII? and reduces CaMKII? synaptosomal accumulation. To our knowledge, it is for the first time to show the cellular function regulation of CaMKII? by GSNOR-dependent S-nitrosation as a new post-translational modification after its phosphorylation was explored. These findings elucidate a novel mechanism of age-related cognitive impairment and may provide a new potential target and strategy for slowing down this process.

Dataset Information

?2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis.

Publications

β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis.

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